The local treatment of Inflammatory Bowel Diseases (e.g., Crohn's Disease and Ulcerative Colitis) is highly challenging, because conventional dosage forms rapidly release the drug in the upper gastro intestinal tract (GIT). Upon absorption into the blood stream the drug is distributed throughout the human body, resulting in potentially severe side effects. In addition, the drug concentration at the site of action—the inflamed colon—is low, leading to low therapeutic efficacies. To overcome these restrictions, drug release from the dosage form should ideally be suppressed in the stomach and small intestine, but set on as soon as the target site is reached.
Different interesting approaches have been described in the literature to allow for site specific drug delivery to the colon upon oral administration. Generally, a drug reservoir is surrounded by a film coating, which is poorly permeable for the drug in the upper GIT, but becomes permeable as soon as the colon is reached. The change in drug permeability of the film coating might be caused by: (i) the change in the pH of the contents of the GIT (stomach—small intestine—colon), (ii) degradation of the film coating by enzymes, which are secreted by colonic bacteria, or (iii) structural changes in the film coating as soon as the target site is reached (e.g., rupturing after a certain lag time, due to a steadily increasing hydrostatic pressure within the dosage form). Furthermore, drug release might start right after oral administration at a rate which is sufficiently small in order to assure that drug is still present in the dosage form once the colon is reached.
However, great care must be taken, because the conditions in the GIT of a patient suffering from Crohn's Disease or Ulcerative Colitis might significantly differ from those in a healthy subject. In particular, the pH values and transit times within the various GIT segments as well as the quality and quantity of the colonic microflora can be very different from those under physiological conditions. Thus, a dosage form which might reliably deliver a drug specifically to the colon in a healthy subject might fail in a patient. Also, the intra- and inter-variability of the dosage form's performance can be expected to be considerable if the onset of drug release is not induced in the disease state. Recently, an Indigestible polysaccharide (IPS), more particularly a branched polysaccharide containing film coatings has been proposed for colon targeting in Inflammatory Bowel Disease patients. This branched polysaccharide is a water-soluble, indigestible polysaccharide with high fiber contents, obtained from wheat starch. Importantly, it serves as a substrate for enzymes secreted from colonic bacteria present in the feces of patients suffering from Crohn's Disease and Ulcerative Colitis. However, so far, only IPS-based film coatings have been described. In these cases, a drug containing reservoir is surrounded by a continuous film, which avoids premature drug release into the contents of the stomach and small intestine.
Yet, the potential of matrix systems containing an indigestible polysaccharide as colon targeting compound is unknown. The concept of matrix systems is fundamentally different from that of film coated dosage forms. There is no “reservoir—membrane” structure. The drug is more or less homogeneously distributed throughout the dosage form. This type of devices can also be called “monolithic systems” or “one-block-systems”. There is no complete local separation of the drug depot on the one hand side and the release rate controlling film coating on the other hand side. In these cases, the drug is embedded within the release rate controlling material. Since IPS as well as the most frequently used drug for the local treatment of Inflammatory Bowel Diseases [5-aminosalicylic acid (5-ASA)] are water soluble at 37° C., an additional, water-insoluble excipient is needed, for instance a lipid. MMX® is a technology used in the commercial product Lialda® aiming at colon specific delivery of 5-ASA. The idea is to embed the drug within a lipid matrix (carnauba wax and stearic acid) and to disperse this phase within a hydrogel consisting mainly of sodium carboxymethylcellulose and sodium starch glycolate. The drug-lipid-hydrogel mixture is compressed into tablets, which are film coated with Eudragit® S and Eudragit® L. Thus, this system requires a coating step and it is a single unit dosage form, suffering from the all-or-nothing effect and an eventually non-homogeneous distribution within the contents of the GIT.
The aim of the invention was to prepare and characterize novel, multiparticulate dosage forms (matrix pellets and mini tablets) usable uncoated or coated and containing the colon targeting compound IPS and high doses of an active agent such as 5-ASA. The high drug content is of major practical importance, because up to 4.8 g 5-ASA is administered per day. Different types of lipids were added to minimize premature drug release in the upper GIT and the effects of various formulation and processing parameters were studied.
The present invention also relates to a method for producing such controlled release composition.